Avenues for Strengthening PCORnet's Capacity to Advance Patient-Centered Economic Outcomes in Patient-Centered Outcomes Research (PCOR).

PCORnet, the National Patient-Centered Clinical Research Network, provides the ability to conduct prospective and observational pragmatic research by leveraging standardized, curated electronic health records data together with patient and stakeholder engagement. PCORnet is funded by the Patient-Centered Outcomes Research Institute (PCORI) and is composed of 8 Clinical Research Networks that incorporate at total of 79 health system "sites." As the network developed, linkage to commercial health plans, federal insurance claims, disease registries, and other data resources demonstrated the value in extending the networks infrastructure to provide a more complete representation of patient's health and lived experiences. Initially, PCORnet studies avoided direct economic comparative effectiveness as a topic. However, PCORI's authorizing law was amended in 2019 to allow studies to incorporate patient-centered economic outcomes in primary research aims. With PCORI's expanded scope and PCORnet's phase 3 beginning in January 2022, there are opportunities to strengthen the network's ability to support economic patient-centered outcomes research. This commentary will discuss approaches that have been incorporated to date by the network and point to opportunities for the network to incorporate economic variables for analysis, informed by patient and stakeholder perspectives. Topics addressed include: (1) data linkage infrastructure; (2) commercial health plan partnerships; (3) Medicare and Medicaid linkage; (4) health system billing-based benchmarking; (5) area-level measures; (6) individual-level measures; (7) pharmacy benefits and retail pharmacy data; and (8) the importance of transparency and engagement while addressing the biases inherent in linking real-world data sources.

MicroRNA Expression in the Infarcted Heart Following Neonatal Cardiovascular Progenitor Cell Transplantation in a Sheep Model of Stem Cell-Based Repair.

Myocardial infarctions affect approximately 735,000 people annually in the United States and have a substantial impact on quality of life. Neonates have an enhanced capability of repairing cardiovascular damage, while adults do not. The mechanistic basis for this age-dependent difference in regenerative capacity remains unknown. Recent studies have shown that microRNAs (miRNAs) play a significant role in regulating the regenerative ability of cardiovascular cells. This report defines the alterations in miRNA expression within the cardiovascular repair zone of infarcted sheep hearts following intracardiac injection of neonatal islet-1+ cardiovascular progenitor cells. Sheep were infarcted via left anterior descending coronary artery ligation. After 3 to 4 weeks of infarction, sheep neonatal islet-1+ cardiovascular progenitor cells were injected into the infarcted area for repair. Cell-treated sheep were euthanized 2 months following cell injection, and their hearts were harvested for the analysis of miRNA and gene expression within the cardiovascular repair zone. Ten miRNAs were differentially regulated in vivo, including miR-99, miR-100, miR-302a, miR-208a, miR-665, miR-1, miR-499a, miR-34a, miR-133a, and miR-199a. These miRNAs promote stemness, cell division, and survival. Several signaling pathways are regulated by these miRNAs, including Hippo, Wnt, and Erythroblastic Leukemia Viral Oncogene B (ERBB). Transcripts encoding Wnt, ERBB, and Neuregulin 1 (NRG1) were elevated in vivo in the infarct repair zone. Wnt5a signaling and ERBB/NRG1 transcripts contribute to activation of Yes-Associated Protein 1. MiRNAs that impact proliferation, cell survival, and signaling pathways that promote regeneration were induced during cardiovascular repair in the sheep model. This information can be used to design new approaches for the optimization of miRNA-based treatments for the heart.

The Impact of Spaceflight and Microgravity on the Human Islet-1+ Cardiovascular Progenitor Cell Transcriptome.

Understanding the transcriptomic impact of microgravity and the spaceflight environment is relevant for future missions in space and microgravity-based applications designed to benefit life on Earth. Here, we investigated the transcriptome of adult and neonatal cardiovascular progenitors following culture aboard the International Space Station for 30 days and compared it to the transcriptome of clonally identical cells cultured on Earth. Cardiovascular progenitors acquire a gene expression profile representative of an early-stage, dedifferentiated, stem-like state, regardless of age. Signaling pathways that support cell proliferation and survival were induced by spaceflight along with transcripts related to cell cycle re-entry, cardiovascular development, and oxidative stress. These findings contribute new insight into the multifaceted influence of reduced gravitational environments.

Outcomes among pediatric patients with cancer who are treated on trial versus off trial: A matched cohort study.

BACKGROUND: Approximately 50% of children with cancer in the United States who are aged <15 years receive primary treatment on a therapeutic clinical trial. To the authors' knowledge, it remains unknown whether trial enrollment has a clinical benefit compared with the best alternative standard therapy and/or off trial (ie, clinical trial effect). The authors conducted a retrospective matched cohort study to compare the morbidity and mortality of pediatric patients with cancer who are treated on a phase 3 clinical trial compared with those receiving standard therapy and/or off trial. METHODS: Subjects were aged birth to 19 years; were diagnosed between 2000 and 2010 with acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), rhabdomyosarcoma, or neuroblastoma; and had received initial treatment at the Children's Hospital of Philadelphia. On-trial and off-trial subjects were matched based on age, race, ethnicity, a diagnosis of Down syndrome (for patients with ALL or AML), prognostic risk level, date of diagnosis, and tumor type. RESULTS: A total of 428 participants were matched in 214 pairs (152 pairs for ALL, 24 pairs for AML, 32 pairs for rhabdomyosarcoma, and 6 pairs for neuroblastoma). The 5-year survival rate did not differ between those treated on trial versus those treated with standard therapy and/or off trial (86.9% vs 82.2%; P = .093). On-trial patients had a 32% lower odds of having worse (higher) mortality-morbidity composite scores, although this did not reach statistical significance (odds ratio, 0.68; 95% confidence interval, 0.45-1.03 [P = .070]). CONCLUSIONS: There was no statistically significant difference in outcomes noted between those patients treated on trial and those treated with standard therapy and/or off trial. However, in partial support of the clinical trial effect, the results of the current study indicate a trend toward more favorable outcomes in children treated on trial compared with those treated with standard therapy and/or off trial. These findings can support decision making regarding enrollment in pediatric phase 3 clinical trials.

Surgical palliation or primary transplantation for aortic valve atresia.

OBJECTIVE: The study objective was to describe the surgical pathway progression through adolescence of an inception cohort of neonates with aortic valve atresia managed initially with surgical palliation or primary transplantation, comparing survival and self-reported health-related quality of life. METHODS: From 1994 to 2000, 565 neonates with aortic atresia were admitted to 26 Congenital Heart Surgeons' Society hospitals and followed annually for vital status. Initial management included surgical palliation (n = 453) and primary cardiac transplantation (n = 68). PedsQL health-related quality of life questionnaires were sent cross-sectionally to a subgroup of 198 patients alive at previous follow-up, with 80 responses. RESULTS: Risk of death was initially high for both treatment strategies. However, compared with initial surgical palliation, survival with primary transplantation, including wait-list mortality, was greater and persisted long-term (65% vs 40% at 15 years; P = .002). Survival after secondary transplantation (48% at 9 years) was lower than after primary transplantation (74%). Health-related quality of life total score was lower overall than that of the general adolescent population (71 ± 16 vs 84 ± 13; P = .0001; normal = 100), but similar to that of adolescents with chronic diseases. It was similar in the surgical palliation and primary transplantation groups (70 ± 16 vs 75 ± 15; P = .3). Patients who received surgical palliation reported more symptoms (76 ± 15 vs 63 ± 18; P = .02). CONCLUSIONS: Patients receiving primary heart transplantation for aortic atresia in 1994 to 2000 experienced better survival, fewer symptoms, and equivalent quality of life compared with those undergoing initial surgical palliation. Notwithstanding the limited availability of neonatal and infant donor hearts, primary transplantation may be considered for those neonates with risk factors predictive of exceptionally poor survival after surgical palliation.

Increased sensitivity to ischemic interval of donor hearts with diminished left ventricular function.

BACKGROUND: Previous studies have demonstrated that carefully selected donor hearts (DHs) with poor left ventricular ejection fraction (EF) may be transplanted with long-term survival equivalent to hearts with normal function. The purpose of this study is to facilitate their selection. METHODS: Using the United Network for Organ Sharing database, we reviewed all adult heart transplants between January 2000 and March 2016. Regression models were developed to estimate hazard ratios with 95% confidence intervals of post-transplant 1-year mortality and failure of EF to recover at 1 year for DHs with EF ≥50%, EF 40%-49.9%, and EF 30%-30.9%. RESULTS: During the study period, 31,979 DHs were transplanted. Compared with DHs with left ventricular ejection fraction ≥50%, DHs with reduced EF were younger and had slightly lower body mass index. There were no differences in the mechanism of death between groups and no differences in recipient characteristics, except for a higher incidence of African American recipients of hearts with an EF of 40%-49.9%. Of the variables analyzed, only a 1-hour increase in ischemia time had different hazard ratios for 1-year mortality between groups, with increasing hazard as EF diminished. It was also the only variable that predicted failure of recovery of normal EF and that was in the lowest EF group. CONCLUSIONS: The impact of DH traits associated with adverse outcomes after heart transplantation that we studied are similar between DHs with EF <50% and those with EF ≥50%. However, limiting ischemic time may be even more important for DHs with diminished left ventricular function, particularly at the low end of the EF spectrum.

Primary Transplantation for Congenital Heart Disease in the Neonatal Period: Long-term Outcomes.

BACKGROUND: Primary transplantation was developed in the 1980s as an alternative therapy to palliative reconstruction of uncorrectable congenital heart disease. Although transplantation achieved more favorable results, its utilization has been limited by the availability of donor organs. This review examines the long-term outcomes of heart transplantation in neonates at our institution. METHODS: The institutional pediatric heart transplant database was queried for all neonatal heart transplants performed between 1985 and 2017. Follow-up was obtained from medical records and an annually administered questionnaire. Overall survival and time to development of complications were estimated using the Kaplan Meier method. Univariate and multivariate analyses were performed to identify independent predictors of survival. RESULTS: Heart transplantation was performed in 104 neonates. Median age was 17 days. Hypoplastic left heart syndrome (classic or variant) was the primary diagnosis in 77.8% of patients. Survival at 10 years and 25 years was 73.9% and 55.8%, respectively. At 20 years, freedom from allograft vasculopathy and lymphoproliferative disease was 72.0% and 81.9%, respectively. Freedom from re-transplantation was 81.4% at 20 years. Eight patients (7.6%) developed end-stage renal disease. By multivariate analysis, lower glomerular filtration rate and allograft vasculopathy were the only significant predictors of death. CONCLUSIONS: Neonatal heart transplantation remains a durable therapy with very acceptable long-term survival. Children transplanted in the newborn period have the potential to reach adulthood with minimal need for reintervention.

Effects of Spaceflight and Simulated Microgravity on YAP1 Expression in Cardiovascular Progenitors: Implications for Cell-Based Repair.

Spaceflight alters many processes of the human body including cardiac function and cardiac progenitor cell behavior. The mechanism behind these changes remains largely unknown; however, simulated microgravity devices are making it easier for researchers to study the effects of microgravity. To study the changes that take place in cardiac progenitor cells in microgravity environments, adult cardiac progenitor cells were cultured aboard the International Space Station (ISS) as well as on a clinostat and examined for changes in Hippo signaling, a pathway known to regulate cardiac development. Cells cultured under microgravity conditions, spaceflight-induced or simulated, displayed upregulation of downstream genes involved in the Hippo pathway such as YAP1 and SOD2. YAP1 is known to play a role in cardiac regeneration which led us to investigate YAP1 expression in a sheep model of cardiovascular repair. Additionally, to mimic the effects of microgravity, drug treatment was used to induce Hippo related genes as well as a regulator of the Hippo pathway, miRNA-302a. These studies provide insight into the changes that occur in space and how the effects of these changes relate to cardiac regeneration studies.

Interaction Between Ischemic Time and Donor Age on Adult Heart Transplant Outcomes in the Modern Era.

BACKGROUND: We examined the effect of cold ischemic interval on modern outcomes to determine whether advances in patient management have made an impact. METHODS: Using the United Network of Organ Sharing database, we reviewed adult heart transplants between January 2000 and March 2016. We divided donor age into terciles: younger than 18 years, 18 to 33 years, and 34 years and older. Within each tercile, transplants were divided by cold ischemic interval of less than 4 hours, 4 to 6 hours, and more than 6 hours. Survival curves were compared between cold ischemic interval categories within each tercile. Covariate-adjusted and donor age-stratified Cox proportional hazards regression models were used to estimate overall mortality and graft failure hazards ratios. RESULTS: Of 29,192 transplants, no significant differences between cold ischemic interval groups in survival or graft failure were apparent in the group aged younger than 18. For donors older than 18, significant differences were found for survival and graft failure with cold ischemic interval exceeding 4 hours in both univariate and multivariate analysis, and survival functions at different ischemic intervals continued to diverge beyond 1 year. The interaction effect between donor age and cold ischemic interval on overall mortality was not significant when analyzed as continuous variables, however younger donor age appeared to attenuate increase in overall mortality with longer cold ischemic intervals. CONCLUSIONS: Despite advances in perioperative management during the past 30 years, for donors older than 18 years, cold ischemic interval exceeding 4 hours is associated with gradual but significantly diminished survival that persists well beyond the perioperative period. Comparison to historical data suggests that advances in management have somewhat attenuated the hazard associated with longer ischemic times.

Long-term transplant outcomes of donor hearts with left ventricular dysfunction.

OBJECTIVE: Despite small single-center reports demonstrating acceptable outcomes using donor hearts with left ventricular dysfunction, 19% of potential donor hearts are currently unused exclusively because of left ventricular dysfunction. We investigated modern long-term survival of transplanted donor hearts with left ventricular dysfunction using a large, diverse cohort. METHODS: Using the United Network for Organ Sharing database, we reviewed all adult heart transplants between January 2000 and March 2016. Baseline and postoperative characteristics and Kaplan-Meier survival curves were compared. A covariates-adjusted Cox regression model was developed to estimate post-transplant mortality. To address observed variation in patient profile across donor ejection fraction, a propensity score was built using Cox predictors as covariates in a generalized multiple linear regression model. All the variables in the original Cox model were included. For each recipient, a predicted donor ejection fraction was generated and exported as a new balancing score that was used in a subsequent Cox model. Cubic spline analysis suggested that at most 3 and perhaps no ejection fraction categories were appropriate. Therefore, in 1 Cox model we added donor ejection fraction as a grouped variable (using the spline-directed categories) and in the other as a continuous variable. RESULTS: A total of 31,712 donor hearts were transplanted during the study period. A total of 742 donor hearts were excluded for no recorded left ventricular ejection fraction, and 20 donor hearts were excluded for left ventricular ejection fraction less than 20%. Donor hearts with reduced left ventricular ejection fraction were from younger donors, more commonly male donors, and donors with lower body mass index than normal donor hearts. Recipients of donor hearts with reduced left ventricular ejection fraction were more likely to be on mechanical ventilation. Kaplan-Meier curves revealed no significant differences in recipient survival up to 15 years of follow-up (P = .694 log-rank test). Cox regression analysis showed that after adjustment for propensity variation, transplant year, and region, ejection fraction had no statistically significant impact on mortality when analyzed as a categoric or continuous variable. Left ventricular ejection fraction at approximately 1 year after transplantation was normal for all groups. CONCLUSIONS: Carefully selected donor hearts with even markedly diminished left ventricular ejection fraction can be transplanted with long-term survival equivalent to normal donor hearts and therefore should not be excluded from consideration on the basis of depressed left ventricular ejection fraction alone. Functional recovery of even the most impaired donor hearts in this study suggests that studies of left ventricular function in the setting of brain death should be interpreted cautiously.

Subaortic Stenosis Resection in Children: Emphasis on Recurrence and the Fate of the Aortic Valve.

BACKGROUND: Recurrence after surgical resection of discrete subvalvar aortic stenosis in children often requires repeat operation. Risk factors for recurrence are poorly understood. We sought to determine potential risk factors for recurrence and postoperative comorbidities in the long term. METHODS: Retrospective chart review was performed on all pediatric patients who underwent surgical resection of discrete subaortic stenosis at our institution. Demographics, perioperative findings, and clinical data were analyzed for predisposing factors. RESULTS: From 1991 to 2015, a total of 104 patients underwent primary surgical resection of discrete subaortic stenosis. There were no postoperative deaths. Three (2.9%) patients required pacemaker implantation. Nine (8.4%) patients required repeat resection for recurrence of subaortic membrane over a median follow-up of 8.5 years (interquartile range: 5.9-13.5 years). Actuarial freedom from repeat resection was 100%, 94%, and 82% at one, five, and ten years, respectively. Repeat resection occurred more frequently in patients with genetic disease (37.5% vs 10.7%; P = .033) and preoperative mitral regurgitation (MR; 25% vs 1.2%; P < .001). Postoperative aortic insufficiency (AI) that was moderate or worse was associated with older age at the time of first resection (relative risk [RR]: 1.54, P < .05), moderate or severe preoperative AI (RR: 1.84, P = .002), and repeat resection of subaortic stenosis (RR: 1.90, P < .001). CONCLUSION: The majority of children who undergo surgical resection of subaortic stenosis will not experience recurrence in childhood and those who do require repeat resection may have a higher incidence of genetic disease and preoperative MR. Postoperative AI is associated with repeat resection, older age at the time of surgery, and degree of preoperative AI.

Cardiovascular progenitor cells cultured aboard the International Space Station exhibit altered developmental and functional properties.

The heart and its cellular components are profoundly altered by missions to space and injury on Earth. Further research, however, is needed to characterize and address the molecular substrates of such changes. For this reason, neonatal and adult human cardiovascular progenitor cells (CPCs) were cultured aboard the International Space Station. Upon return to Earth, we measured changes in the expression of microRNAs and of genes related to mechanotransduction, cardiogenesis, cell cycling, DNA repair, and paracrine signaling. We additionally assessed endothelial-like tube formation, cell cycling, and migratory capacity of CPCs. Changes in microRNA expression were predicted to target extracellular matrix interactions and Hippo signaling in both neonatal and adult CPCs. Genes related to mechanotransduction (YAP1, RHOA) were downregulated, while the expression of cytoskeletal genes (VIM, NES, DES, LMNB2, LMNA), non-canonical Wnt ligands (WNT5A, WNT9A), and Wnt/calcium signaling molecules (PLCG1, PRKCA) was significantly elevated in neonatal CPCs. Increased mesendodermal gene expression along with decreased expression of mesodermal derivative markers (TNNT2, VWF, and RUNX2), reduced readiness to form endothelial-like tubes, and elevated expression of Bmp and Tbx genes, were observed in neonatal CPCs. Both neonatal and adult CPCs exhibited increased expression of DNA repair genes and paracrine factors, which was supported by enhanced migration. While spaceflight affects cytoskeletal organization and migration in neonatal and adult CPCs, only neonatal CPCs experienced increased expression of early developmental markers and an enhanced proliferative potential. Efforts to recapitulate the effects of spaceflight on Earth by regulating processes described herein may be a promising avenue for cardiac repair.

Role of Negative Pressure Wound Care and Hyperbaric Oxygen Therapy for Sternal Wound Infections After Pediatric Cardiac Surgery.

BACKGROUND: Sternal wound infections after pediatric cardiac surgery are uncommon but can be morbid. METHODS: We describe an institutional protocol for complicated sternal wounds utilizing hyperbaric oxygen therapy (HBO) and negative pressure wound therapy (NPWT). PARTICIPANTS: A retrospective chart review (2001-2013) of 4,028 pediatric cardiac operations in 3,264 patients less than 18 years of age. RESULTS: Fifty-three patients (1.62%; 53/3,264) were diagnosed with clinical sternal wound infections. There were 27 (50.9%) males and 26 (49.1%) females. Thirty-seven (69.8%) patients received antibiotics and/or debridement; sixteen (30.2%) patients had more complicated infections requiring NPWT and/or HBO therapy. The time to heal for wounds treated with HBO and HBO + NPWT was a mean of 43.75 (±24.27) days (range: 21-98 days; median: 35 days). Among all infected patients, the time from diagnosis of the infection to resolution of the infection for all survivors was 7 to 98 days (mean: 26.41 days; median: 21 days). Forty-eight (90.6%) patients completely healed their wounds, and 45 (84.9%) patients are currently alive. Thirty-eight patients had a cyanotic cardiac diagnosis and 15 had an acyanotic cardiac diagnosis. The most common bacteria isolated from the blood or wound cultures was Staphylococcus aureus. Six of 53 patients died. Causes of death are as follows: three from respiratory failure, one from sepsis, one from hypoxic ischemic encephalopathy, and one from exsanguination leading to cardiac arrest Conclusions: Complicated sternal wound infections after pediatric cardiac surgery refractory to antibiotic therapy and/or debridement can be successfully treated with NPWT and/or HBO therapy.

Short-term hypoxia improves early cardiac progenitor cell function in vitro.

The use of cardiovascular progenitor cells (CPCs) to repair damaged myocardium has been the focus of intense research. Previous reports have shown that pretreatments, including hypoxia, improve cell function. However, the age-dependent effects of short-term hypoxia on CPCs, and the role of signaling in these effects, are unknown. Cloned neonatal and adult CPCs expressing Isl1, c-Kit, KDR, PDGFRA, and CXCR4, were preconditioned using hypoxia (1% O2 for six hours). Intracellular signaling pathway changes were modeled using Ingenuity Pathway Analysis (IPA), while qRT-PCR, flow cytometry, and immunoblotting were used to measure pathway activation. Cellular function, including survival, cell cycle, and invasion, were evaluated using a TUNEL assay, flow cytometry, and a Transwell® invasion assay, respectively. IPA predicted, and RT-PCR and flow cytometry confirmed, that the PI3K/AKT pathway was activated following short-term hypoxia. Heat shock protein (HSP) 40 expression increased significantly in both age groups, while HSP70 expression increased only in neonatal CPCs. Neonatal CPC invasion and survival improved after hypoxia pre-treatment, while no effect was observed in cell cycling and developmental status. Prostaglandin receptor expression was enhanced in neonatal cells. Prior to transplantation, hypoxic preconditioning enhances CPC function, including invasion ability and pro-survival pathway activation.

Neonatal heart transplantation.

Neonatal heart transplantation was developed and established in the 1980's as a durable modality of therapy for complex-uncorrectable heart disease. Patients transplanted in the neonatal period have experienced unparalleled long-term survival, better than for any other form of solid-organ transplantation. However, the limited availability of neonatal and young infant donors has restricted the indications and applicability of heart transplantation among newborns in the current era. Indications for heart transplantation include congenital heart disease not amenable to other forms of surgical palliation, and cardiomyopathy, including some primary tumors. Use of ABO-incompatible transplants, and organs with prolonged cold ischemic time or marginal function have all been associated with good outcomes in infants. These extended strategies to increase the donor pool may also someday include donation after determination of circulatory death and the use of anencephalic donors. The operative techniques for donors and recipients of neonatal heart transplantation are unique and have been well-described. Immunosuppression protocols for neonates need not include induction and are largely steroid-free. Newborn and young infant transplant recipients have fewer episodes of rejection, less coronary allograft vasculopathy, less post-transplant lymphoproliferative disease and less renal dysfunction than their older counterparts. Long-term outcomes have been very encouraging in terms of graft survival, patient survival, and quality of life. Our review highlights the history, current indications, techniques and outcomes of heart transplantation in this immunologically-privileged subset of patients.

Spaceflight Activates Protein Kinase C Alpha Signaling and Modifies the Developmental Stage of Human Neonatal Cardiovascular Progenitor Cells.

Spaceflight impacts cardiovascular function in astronauts; however, its impact on cardiac development and the stem cells that form the basis for cardiac repair is unknown. Accordingly, further research is needed to uncover the potential relevance of such changes to human health. Using simulated microgravity (SMG) generated by two-dimensional clinorotation and culture aboard the International Space Station (ISS), we assessed the effects of mechanical unloading on human neonatal cardiovascular progenitor cell (CPC) developmental properties and signaling. Following 6-7 days of SMG and 12 days of ISS culture, we analyzed changes in gene expression. Both environments induced the expression of genes that are typically associated with an earlier state of cardiovascular development. To understand the mechanism by which such changes occurred, we assessed the expression of mechanosensitive small RhoGTPases in SMG-cultured CPCs and observed decreased levels of RHOA and CDC42. Given the effect of these molecules on intracellular calcium levels, we evaluated changes in noncanonical Wnt/calcium signaling. After 6-7 days under SMG, CPCs exhibited elevated levels of WNT5A and PRKCA. Similarly, ISS-cultured CPCs exhibited elevated levels of calcium handling and signaling genes, which corresponded to protein kinase C alpha (PKCα), a calcium-dependent protein kinase, activation after 30 days. Akt was activated, whereas phosphorylated extracellular signal-regulated kinase levels were unchanged. To explore the effect of calcium induction in neonatal CPCs, we activated PKCα using hWnt5a treatment on Earth. Subsequently, early cardiovascular developmental marker levels were elevated. Transcripts induced by SMG and hWnt5a-treatment are expressed within the sinoatrial node, which may represent embryonic myocardium maintained in its primitive state. Calcium signaling is sensitive to mechanical unloading and directs CPC developmental properties. Further research both in space and on Earth may help refine the use of CPCs in stem cell-based therapies and highlight the molecular events of development.

An Absorbable Hydrogel Spray Reduces Postoperative Mediastinal Adhesions After Congenital Heart Surgery.

BACKGROUND: Adhesions encountered during reoperative cardiac surgery can prolong operative time and increase operative risk. The purpose of this clinical study was to investigate the antiadhesion property of a synthetic bioabsorbable polymer spray after cardiac reoperations in infants. METHODS: A prospective randomized double-blinded study was designed. Forty infants requiring staged cardiac operations were randomly allocated to a study group (n = 20) or a control group (n = 20). The appropriate volume of the polymer was sprayed onto the mediastinal surfaces before chest closure after the first surgical procedure in the study group. At reoperation, adhesions were evaluated by a blinded investigator following a 5-grade scoring system. Five predetermined anatomic areas were scored. Incision to extracorporeal circulation time was also analyzed. RESULTS: In all, 40 subjects were enrolled into the study. Four babies died before the second operation. Three others were missed for reevaluation. The control group (n = 16) had longer incision to extracorporeal circulation time (38 ± 10 minutes) than the study group (n = 17; 23 ± 6 minutes; p < 0.001). The control subjects had significantly more severe adhesions than the study group at all five mediastinal areas: (1) retrosternal (p < 0.001); (2) base of the heart (large vessels [p < 0.05]); (3) right side (p < 0.01); (4) left side (p < 0.02); and (5) diaphragmatic side of the mediastinum (p < 0.001). CONCLUSIONS: The use of synthetic bioabsorbable polymer sealant spray at the end of primary pediatric cardiac surgery reduces the intensity of mediastinal adhesions and the reentry time in infants undergoing repeat median sternotomy.

Effect of left ventricular dysfunction on utilization of donor hearts.

BACKGROUND: In this study we investigated modern, non-utilization rates of potential cardiac donors with left ventricular dysfunction (LVD) to clarify this phenomenon's magnitude and the impact of recent studies suggesting these organs can be safely transplanted. METHODS: Using the United Network for Organ Sharing transplant database, we reviewed all donors evaluated between January 1, 2007 and June 30, 2014. Exclusion criteria included lack of consent and age <13 or >59 years. The number of hearts not transplanted due to non-cardiac causes, structural disease, "other" (previous cardiac surgery, donation after cardiac death, etc.) and isolated LVD was determined and a covariates-adjusted Poisson regression model with robust standard errors was developed to estimate non-utilization relative risk (RR) with 95% confidence interval (CI) for LVD. Heart disposition for potential donor hearts was determined separately for 2 previous eras (1990 to 1999 and 2000 to 2006), and trends were evaluated. RESULTS: There were 60,789 donors assessed. Of the 44,829 organs meeting the inclusion criteria, 15,654 (34.92%) were transplanted and 29,175 (65.08%) were not. Of the non-utilized hearts, 15,512 (34.60%) were declined for non-cardiac reasons, 1,051 (2.34%) for structural disease, 4,073 (9.09%) for "other" and 8,539 (19.05%) exclusively for LVD. Of this last category, 4,950 (11.04%) lacked documented evidence of LVD. Covariates-adjusted RR for non-utilization showed that, for every 10% increase in LV ejection fraction, the risk of non-utilization decreased by 20% (RR = 0.80, 95% CI 0.79 to 0.81). Analysis of era-effect demonstrated significantly decreased overall utilization of donor hearts, with increases in the number of hearts not transplanted across all categories over time (p < 0.001). CONCLUSIONS: Roughly 20% of potential cardiac donors are excluded due to LVD. This figure has not been impacted by recent studies indicating that these hearts may be used safely. More complete data are required to understand why 11.04% of hearts that met inclusion criteria were refused for "poor function" without documented evidence.

A Hyper-Crosslinked Carbohydrate Polymer Scaffold Facilitates Lineage Commitment and Maintains a Reserve Pool of Proliferating Cardiovascular Progenitors.

BACKGROUND: Cardiovascular progenitor cells (CPCs) have been cultured on various scaffolds to resolve the challenge of cell retention after transplantation and to improve functional outcome after cell-based cardiac therapy. Previous studies have reported successful culture of fully differentiated cardiomyocytes on scaffolds of various types, and ongoing efforts are focused on optimizing the mix of cardiomyocytes and endothelial cells as well as on the identification of a source of progenitors capable of reversing cardiovascular damage. A scaffold culture that fosters cell differentiation into cardiomyocytes and endothelial cells while maintaining a progenitor reserve would benefit allogeneic cell transplantation. METHODS: Isl-1 + c-Kit + CPCs were isolated as clonal populations from human and sheep heart tissue. After hyper-crosslinked carbohydrate polymer scaffold culture, cells were assessed for differentiation, intracellular signaling, cell cycling, and growth factor/chemokine expression using real time polymerase chain reaction, flow cytometry, immunohistochemistry, and calcium staining. RESULTS: Insulin-like growth factor 1, hepatocyte growth factor, and stromal cell derived factor 1α paracrine factors were induced, protein kinase B signaling was activated, extracellular signal-regulated kinase phosphorylation was reduced and differentiation into both cardiomyocytes and endothelial cells was induced by scaffold-based cell culture. Interestingly, movement of CPCs out of the G1 phase of the cell cycle and increased expression of pluripotency genes PLOU5F1 (Oct4) and T (Brachyury) within a portion of the cultured population occurred, which suggests the maintenance of a progenitor population. Two-color immunostaining and 3-color fluorescence-activated cell sorting analysis confirmed the presence of both Isl-1 expressing undifferentiated cells and differentiated cells identified by troponin T and von Willebrand factor expression. Ki-67 labeling verified the presence of proliferating cells that remained in situ alongside the differentiated functional derivatives. CONCLUSIONS: Cloned Isl-1 + c-kit + CPCs maintained on a hyper-cross linked polymer scaffold retain dual potential for proliferation and differentiation, providing a scaffold-based stem cell source for transplantation of committed and proliferating cardiovascular progenitors for functional testing in preclinical models of cell-based repair.